The proposed program project is based on our central hypothesis that Wiskott-Aldrich syndrome protein (WASP), its homologue N-WASP, and its partner WASP interactive protein (WIP), are involved in cytoskeletal re-organization and gene induction upon activation of blood cells. Toward this end we targeted the genes encoding all these proteins by homologous recombination. We plan to exploit these knock-outs to elucidate the pathway(s) from cell surface receptors to cytoskeletal re-organization in T cells, B cells and platelets. The proposal consists of four projects and two cores. Project 1 (R. Geha) seeks to understand the overlapping and non-overlapping roles of WASP, WIP and the WASP-WIP complex in T cell activation and cytoskeletal reorganization. Project 2 (S. Snapper and F. Alt) and Project 3 (L. Notarangelo) will dissect the role of WASP, N-WASP and WIP in T and B cell function respectively. Project 4 (John Hartwig) will examine the role of WASP, N-WASP and WIP in maintaining platelet homeostasis. Core A will administer the program. Core B will provide genetically engineered mice and generate monoclonal antibodies for all four projects.